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1、AGA technical review on hereditary colorectal cancer and genetic testingThis literature review and the recommendations therein were prepared for the American Gastroenterological Association (AGA) Clinical Practice and Practice Economics Committee. The paper was approved by the Committee on March 20,
2、 2001, and by the AGA Governing Board on April 18, 2001. GASTROENTEROLOGY 2001;121:198-213Colorectal cancer is a major American health problem, ranking as the second leading cause of cancer death, after lung cancer, in the United States. About 129,400 new cases are diagnosed each year, and 56,600 Am
3、ericans die annually from this disorder.1The etiology of colorectal cancer is heterogeneous, with environment or genetics playing varying key roles in different patients.2 About 80% of patients with colorectal cancer seem to have sporadic disease with no evidence of having inherited the disorder. In
4、 the remaining 20%, there seems to be a potentially definable genetic component. Evidence for a genetic contribution to colorectal cancer includes increased risk of colorectal malignancy in persons with a family history and familial aggregation of colorectal cancer consistent with autosomal dominant
5、 inheritance.3,4 In the past decade, germline genetic mutations conferring high lifetime risk of colorectal cancer in carriers have been found, accounting for 5%-6% of all colorectal cancer cases. Other gene mutations, some with lower lifetime risks, are continuing to be characterized.The translatio
6、n into clinical practice of genetic discoveries related to hereditary colorectal cancer continues apace, primarily through improved risk assessment by genetic testing. When used appropriately, genetic testing for hereditary forms of colorectal cancer can confirm or reject the diagnosis at the molecu
7、lar level, justify surveillance of at-risk persons, decrease the cost of surveillance by risk stratification, aid in surgical and chemoprevention management, and help in decisions regarding family and career planning. But when used inappropriately, genetic testing has the potential to misinform affe
8、cted patients with false-negative results.5This technical review critically analyzes currently available literature and: (1) succinctly reviews the known colorectal cancer genetic syndromes of familial adenomatous polyposis (FAP) and hereditary nonpolyposis colorectal cancer (HNPCC) and variants, (2
9、) analyzes the current availability and cost of genetic tests, and (3) describes indications for use of genetic tests in the hereditary colorectal cancer syndromes.Literature reviewGeneral information Study identification and selection A systematic computer-aided search of MEDLINE and Current Conten
10、ts from January 1966 to December 1999 was performed focusing on the major hereditary colorectal cancer syndromes and associated reports of genetic testing. The search identified all literature under the medical subject headings and text words, “familial adenomatous polyposis,” “adenomatous polyposis
11、,” “adenomatous polyposis coli,” “familial polyposis coli,” “hereditary nonpolyposis colorectal syndrome,” “HNPCC,” “Lynch syndrome,” and “gene/genetic testing.” In addition, an extensive manual search was conducted using references from all retrieved reports, review articles, and chapters from gast
12、roenterology textbooks. Data concerning availability and costs of genetic tests were collected by a search of GeneTests, www.genetests.org , and by telephone survey of specific laboratories. Publications and other information were retrieved, and the authors synthesized and assessed the quality of th
13、e available data with respect to topicality and currency. Differences among reviewers concerning inclusion were resolved by consensus. Editorials and letters to the editor were excluded from this review.Review of inherited colorectal cancer syndromesFAP Clinical features FAP is an autosomal dominant
14、 syndrome caused by germline mutation of the APC (adenomatous polyposis coli) gene.6-8 This disorder is estimated to occur in 1 of 8300 to 1 of 14,025 live births, affects both sexes equally, and has worldwide distribution.9 Characteristically, teenaged patients develop multiple (100) adenomas diffu
15、sely throughout the colon (Figure 1); 50% of FAP patients develop adenomas by 15 years of age and 95% by age 35.10-12 . Fig. 1. Colectomy specimen demonstrating diffuse polyposis, from a patient with FAP.Colorectal cancer is inevitable in FAP patients if colectomy is not performed. The average age a
16、t diagnosis ranges from 34.5 to 43 years.10,13In addition to polyposis coli, patients with FAP can develop a variety of benign extracolonic manifestations (Table 1).These include extracolonic polyps (adenomas of the small intestine and stomach, fundic gland retention polyps of the stomach),14-17 cutaneous lesions (lipomas, fibromas, sebaceous, and epidermoid cysts),18,19 desmoid tumors,20 osteomas,21,22 occult radiopaque jaw lesions,23 dental abnorm
